A number of reports have recently described an unexpected degree of plasticity of stem cells derived from adult animals. These studies showed, for example, that transplantation of hematopoietic cells into irradiated mice leads to their transdifferentiation into muscle, liver and neural cells. However, whether similar processes occur in undisturbed animals remains unclear. This can now be studied with a technique that we recently developed and that allows to trace lineage ancestry in vivo. The technique is based on double transgenic mice in which expression of a lineage specific marker gene is translated into an irreversible DNA change that can be detected by LacZ expression. Using mice in which cells are tagged that express the lysozyme M gene (a myelomonocytic marker), as well as cells that once expressed the marker, we found that myelomonocytic cells are continuously reprogrammed into a subset of functional B lymphocytes. In addition, we discovered that brains of these mice contain a substantial proportion of cells derived from lysozyme expressors. Exploiting the Lysozyme-R-LacZ mouse model, we now propose to find out what the cells are that switch, into what types of brain cells they convert and how this happens during development. We will also use a more general approach to determine the spectrum of tissues in the body into which hematopoietic cells become reprogrammed normally, using mice expressing the pan-hematopoietic marker gene Vav.